Hexokinase
Enzyme Structure The hexokinase family of enzymes serve to phosphorylate various hexoses to hexose-6-phosphate with the addition of ATP. Specific to glucose metabolism is hexokinase D, or glucokinase, a 465 amino acid protein of molecular weight 50 kD (1). Glucokinase’s primary function exists at the beginning of glycolysis and glycogen formation as glucokinase phosphorylates glucose to glucose-6-phosphate by the reaction: Glucokinase in its active form exists as a homodimer. Each monomer consists of two β-sheets flanked by an α-helix. These two β-sheets together form the basis of the interaction that makes up the dimer, attracting each monomer to the other (1). Normal Function Within the β-sheets, nearly ten residues contribute to hydrogen bonding that binds glucose to the active site. Near to this, two residues, Thr-233 and Ser-418 bind a sulfate ion that has affinity for the α-phosphate of ATP, holding ATP in place (Figure 1). The γ-phosphate is transferred to glucose, forming glucose-6-phosphate which along with ADP are subsequently released from the active site (1). Observations in Alzheimer's Disease Normal activity of hexokinase is essential for the commencement of glycolysis and glycogen formation. In Alzheimer’s disease, there have been mixed findings of hexokinase activity. A 1989 study by Marcus et al. found that decreased cellular uptake of glucose in Alzheimer’s patients was due to decreased activity of hexokinase (2). By exposing brain samples from four AD patients and eight healthy controls to radiolabelled glucose, the researchers compared the levels of radiolabelled glucose-6-phosphate between groups. The researchers found a significant 34% decrease in hexokinase specific activity in AD patients (p<0.01) (2). However, it is possible that such a small sample size does not sufficiently account for random error, causing potentially misleading results. In an earlier study by Iwangoff et al., the researchers found that HK demonstrated increased activity in patients with dementia, Alzheimer’s or otherwise, when compared to healthy age-matched controls (3). Examining another relatively small sample (n=20), Iwangoff et al. found an activity of 4.39 umol/min in healthy controls compared to 4.93 umol/min in AD patients (p<0.01). This was based on a linear regression model for HK’s KM value. It should be noted that the r value for this constant was r=0.439, suggesting a large degree of uncertainty in specific activity calculations not accounted for in their calculations. Evidently, conflicting results regarding HK activity in AD patients suggests a degree of uncertainty in the role of HK in decreasing glycolytic activity in AD patients. In the study by Bigl et al, the authors found no significant difference in hexokinase activity between healthy individuals and those with Alzheimer’s (4). As depicted in Figure 2, controls and AD samples exhibit similar hexokinase activity in six different areas of the brain. Furthermore, this paper is the last published study regarding HK activity in AD patients. While this does not completely rule out a role of HK in AD progression, it does suggest that no significant positive results have been observed since 1999. Combined with mixed results observed above, hexokinase activity is unlikely to be consistently significantly altered in diseased patients compared to controls. ---- Back to homepage. Works Cited 1. Kuettner, E. B., Kettner, K., Keim, A., Svergun, D. I., Volke, D., Singer, D., … Sträter, N. (2010). Crystal structure of hexokinase KlHxk1 of Kluyveromyces lactis: a molecular basis for understanding the control of yeast hexokinase functions via covalent modification and oligomerization. The Journal of biological chemistry, 285(52), 41019–41033. doi:10.1074/jbc.M110.185850 2. Marcus, D. L., De Leon, M. J., Goldman, J., Logan, J., Christman, D. R., Wolf, A. P., … Pearson, J. (1989). Altered glucose metabolism in microvessels from patients with Alzheimer’s disease. Annals of neurology, 26(1), 91–94. doi:10.1002/ana.410260114 3. Iwangoff, P., Armbruster, R., Enz, A., & Meier-Ruge, W. (1980). Glycolytic enzymes from human autoptic brain cortex: normal aged and demented cases. Mechanisms of ageing and development, 14(1-2), 203–209. 4. Bigl, M.; Bruckner, M. K.; Arendt, T.; Bigl, V.; Eschrich, K. Activities of key glycolytic enzymes in the brains of patients with Alzheimer's disease. J Neural Transm 1999, 106, 499-511.